依那朵林 | 124378-77-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 中文名称: 依那朵林
• 英文名称: enadoline
• 英文别名: 2-(1-benzofuran-4-yl)-N-methyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide
• CAS: 124378-77-4
• 化学式: C₂₄H₃₂N₂O₃
• 分子量: 396.53
• InChiKey: JMBYBVLCYODBJQ-HFMPRLQTSA-N

物化性质

• 沸点：
  563.2±50.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)
• 溶解度：
  In water, 1.15 mg/L at 25 °C (est)
• 蒸汽压力：
  1.46X10-8 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  45.9
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

毒理性

• 相互作用

kappa-阿片受体激动剂恩纳多林（Ena）对戊四唑（PTZ）诱导的癫痫、PTZ点燃、穿梭箱行为和海马神经形态学的影响进行了研究。Ena以1和10纳米尔的剂量icv注射，对急性PTZ癫痫发作无影响。在PTZ点燃发展过程中，与kappa-阿片受体激动剂共同治疗（1纳米尔）可抑制癫痫强度。点燃完成后8天，动物接受了PTZ的挑战剂量。对挑战的反应中，预先用Ena处理的点燃动物达到了显著较低的癫痫评分。点燃导致穿梭箱行为减少。预先用Ena处理的点燃动物的学习表现并未恢复正常。点燃导致谷氨酸结合增加。有趣的是，与盐水/盐水组相比，Ena/盐水组和Ena/PTZ处理组在谷氨酸结合方面没有发现变化。这意味着Ena防止了点燃组谷氨酸结合的增加。在点燃动物中发现了背侧海马CA1区的显著细胞丢失，并且Ena有效地对此进行了对抗。然而，Ena单独也诱导了与点燃动物相似的细胞丢失。据推测，恩纳多林的效果主要是由于与谷氨酸能系统的干扰。

... The effects of the kappa-opioid receptor agonist enadoline (Ena) on pentylenetetrazol (PTZ) induced seizures, PTZ kindling, shuttle-box performance and hippocampal neuromorphology /were investigated/. Ena injected icv. in doses of 1 and 10 nmol did not affect acute PTZ seizures. In the course of PTZ kindling development, co-treatment (1 nmol) with the kappa-opioid receptor agonist suppressed seizure strength. Eight days after kindling completion the animals received a challenge dose of PTZ. In reaction to challenge, kindled animals which were pretreated with Ena reached significantly lower seizure scores. Kindling resulted in diminished shuttle-box performance. Learning performance in kindled animals pretreated with Ena was not normalized. Kindling resulted in increased glutamate binding. Interestingly, in comparison with the saline/saline group, neither in the Ena/saline nor in the Ena/PTZ treated groups changes in glutamate binding were found. That means that Ena prevented the increase in glutamate binding in the kindled group. In kindled animals significant cell loss in CA1 of the dorsal hippocampus was found and this was efficaciously counteracted by Ena. However, Ena alone did induce similar cell loss compared to kindled animals. It is hypothesized that the effects of enadoline are mainly due to interferences with glutamatergic systems.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

本研究旨在探讨卡帕阿片受体激动剂恩纳多林和α-肾上腺素受体激动剂可乐定单独或联合使用在利舍平处理的大鼠帕金森病模型中的潜在抗帕金森病效果。大鼠接受利舍平（3 mg/kg）处理，18小时后进行实验，此时它们表现出明显的运动不能（正常动物每小时1251±228移动计数，利舍平处理动物每小时9±2移动计数）。恩纳多林和可乐定均以剂量依赖性方式增加了利舍平处理大鼠的运动能力。恩纳多林单独使用时最大运动刺激效果出现在0.2 mg/kg剂量（每小时208±63移动计数）。可乐定的最大效果出现在2 mg/kg剂量（每小时536±184移动计数）。恩纳多林（0.1 mg/kg）和可乐定（0.01 - 0.1 mg/kg）在亚阈值剂量下联合给药，协同增加了运动能力。在利舍平处理的大鼠中，协同刺激运动涉及激活卡帕阿片受体以及α1和α2-肾上腺素受体的联合作用。

...The aim of this study was to investigate the potential anti-parkinsonian efficacy of the kappa-opioid receptor agonist, enadoline, and the alpha-adrenoreceptor agonist, clonidine, both alone or in combination, in the reserpine-treated rat model of Parkinson's disease. Rats were treated with reserpine (3 mg/kg), and experiments carried out 18 hr later, at which time they exhibited profound akinesia (normal animals 1251+/-228 mobile counts per hr, reserpine-treated animals 9+/-2 mobile counts per hr). Both enadoline and clonidine increased locomotion in reserpine-treated rats in a dose-dependent manner. The maximum locomotor-stimulating effect of enadoline alone was seen at a dose of 0.2 mg/kg (208+/-63 mobile counts/hr). The maximum effect of clonidine was seen at a dose of 2 mg/kg (536+/-184 mobile counts/hr). Co-administration of enadoline (0.1 mg/kg) and clonidine (0.01 - 0.1 mg/kg) at sub-threshold doses, synergistically increased locomotion. The synergistic stimulation of locomotion in the reserpine-treated rat involved activation of kappa-opioid receptors and a combination of both alpha1 and alpha2-adrenoreceptors. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

kappa 受体激动剂恩纳多林（CI-977）对谷氨酸传递的影响在体外进行了研究。恩纳多林以浓度依赖性方式减少了从黑质片断中由 K(+) 触发的谷氨酸释放（最大效果：在 200 微摩尔时抑制了 78%）。这种效果被选择性 kappa 受体拮抗剂诺-比纳尔特芬（nor-binaltorphimine）阻断。kappa 受体的内源性配体被认为是强啡肽。从纹状体-苍白球和纹状体-黑质路径的终端释放的强啡肽可能因此作为内源性调节剂在基底神经节的谷氨酸传递中发挥作用。

The effects of the kappa receptor agonist enadoline (CI-977) on glutamate transmission were investigated in vitro. Enadoline reduced the K(+)-evoked release of glutamate from slices of substantia nigra in a concentration-dependent manner (maximum effect: 78% inhibition at 200 uM). This effect was blocked by the selective kappa receptor antagonist nor-binaltorphimine. The endogenous ligand for kappa receptors is thought to be dynorphin. Dynorphin released from terminals of striato-pallidal and striato-nigral pathways might thus act as an endogenous modulatory agent on glutamatergic transmission in the basal ganglia.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

卡帕阿片受体激动剂能够抑制从中脑边缘多巴胺能神经元释放的多巴胺，并减少 rodents 中可卡因的某些行为效应。证据表明卡帕阿片受体激动剂可能作为可卡因的功能性拮抗剂，这引导了对它们与可卡因滥用相关效应在恒河猴中的相互作用的研究。在可卡因自我给药研究中，四种芳基乙酰胺（U50,488，恩纳多林，(-) 螺旋多林和PD117302）和四种苯吗喃（乙基酮环唑辛 [EKC]，布雷马唑辛，Mr2033和环唑辛）各自作为连续输注给药10天。EKC，Mr2033，布雷马唑辛，U50,488和恩纳多林产生了显著的剂量依赖性和持续的减少可卡因自我给药，并且在某些剂量下也减少了食物维持的响应。在卡帕激动剂治疗的前两天偶尔观察到呕吐和镇静，但对这些效果的耐受性迅速发展。...

Kappa opioid agonists inhibit dopamine release from mesolimbic dopaminergic neurons and attenuate some behavioral effects of cocaine in rodents. Evidence that kappa opioid agonists may act as functional antagonists of cocaine led ... to /the examination of/ their interactions with cocaine's abuse-related effects in rhesus monkeys. In cocaine self-administration studies, four arylacetamides (U50,488, enadoline, (-) spiradoline and PD117302) and four benzomorphans (ethylketocyclazocine [EKC], bremazocine, Mr2033 and cyclazozine) each were administered as continuous infusions over 10 days. EKC, Mr2033, bremazocine, U50,488 and enadoline produced significant dose-dependent and sustained decreases in cocaine self-administration and also decreased food-maintained responding at some doses. Emesis and sedation were occasionally observed during the first two days of kappa agonist treatment, but tolerance developed rapidly to these effects. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

16名健康受试者...接受了单次肌肉注射CI-977（盐酸埃纳多林）(5、15或25微克)或安慰剂，每周一次，根据随机、双盲、安慰剂对照、四周期交叉设计。每次给药后收集系列血液和尿液样本。... CI-977的吸收迅速，个体tmax值范围从0.17到1.5小时。Cmax和AUC(0-无穷大)随剂量成比例增加。... /盐酸埃纳多林/

16 healthy subjects....received single intramuscular doses of CI-977 /(Enadoline hydrochloride)/ (5, 15, or 25 ug) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design. Serial blood and urine specimens were collected after each dose. ... Absorption of CI-977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0-infinity) increased proportionally with dose. ... /Enadoline hydrochloride/

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  在 氯化亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 0.34h， 生成 依那朵林
  参考文献：
  名称：

  A facile synthesis of [14C]enadoline [(5R)-(5α, 7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5] DEC-8-YL]-4-benzofuranacetamide

  摘要：

  4-氯甲基苯并呋喃 (10) 由 2,3-二甲基苯甲醚经 7 步合成。由镁-蒽络合物制备的相应格氏试剂依次与 14CO2、SOCl2 和 PD130812 反应，得到 [14C]enadoline (2)，一种非肽、选择性 κ 阿片受体激动剂。该方法可以很容易地进行修改，以快速、一锅合成[11C]enadoline。

  DOI：

  10.1002/jlcr.2580361208

文献信息

• Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
  申请人：——

  公开号：US20010041726A1

  公开（公告）日：2001-11-15

  The present invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or optionally, at least one therapeutic agent, such as, steroids, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) inhibitors, H antagonists, antineoplastic agents, antiplatelet agents, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The present invention also provides novel compositions comprising at least one parent COX-2 inhibitor and at least one nitric oxide donor, and, optionally, at least one therapeutic agent. The present invention also provides kits and methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity; and for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2.

  本发明描述了新颖的硝化和/或亚硝化环氧合酶2（COX-2）抑制剂以及包含至少一种硝化和/或亚硝化环氧合酶2（COX-2）抑制剂的新型组合物，以及可选地，至少一种捐赠、转移或释放一氧化氮、刺激内源性一氧化氮合成、提高内源性内皮源性舒张因子水平或是一氧化氮合酶底物的化合物，和/或可选地，至少一种治疗剂，如类固醇、非甾体抗炎化合物（NSAID）、5-脂氧合酶（5-LO）抑制剂、白三烯B4（LTB4）受体拮抗剂、白三烯A4（LTA4）水解酶抑制剂、5-HT激动剂、3-羟基-3-甲基戊二酰辅酶A（HMGCoA）抑制剂、H受体拮抗剂、抗肿瘤药物、抗血小板药物、解充血剂、利尿剂、镇静或非镇静抗组胺药、诱导型一氧化氮合酶抑制剂、阿片类药物、镇痛剂、幽门螺杆菌抑制剂、质子泵抑制剂、异前列腺素抑制剂以及其混合物。本发明还提供了包含至少一种母体COX-2抑制剂和至少一种一氧化氮供体的新型组合物，以及可选地，至少一种治疗剂。本发明还提供了用于治疗炎症、疼痛和发热的工具和方法；用于治疗和/或改善COX-2抑制剂的胃肠道特性；用于促进伤口愈合；用于治疗和/或预防肾毒性；以及用于治疗和/或预防由于环氧合酶-2水平升高而导致的其他疾病的工具和方法。
• [EN] OPIOID AGONISTS AND USES THEREOF<br/>[FR] AGONISTES OPIOÏDES ET LEURS UTILISATIONS
  申请人：NEKTAR THERAPEUTICS INDIA PVT LTD

  公开号：WO2015079459A1

  公开（公告）日：2015-06-04

  Provided are compounds, including those of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.

  提供的是化合物，包括公式I的化合物；以及它们的药用可接受盐和溶剂化物。本文所述的化合物与药物发现、药物治疗、生理学、有机化学和聚合物化学等领域有关，并且/或在这些领域有应用。
• Oxime and/or hydrozone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
  申请人：NitroMed, Inc.

  公开号：US20040006133A1

  公开（公告）日：2004-01-08

  The invention describes novel cyclooxygenase 2 (COX-2) selective inhibitors having at least one oxime group or hydrazone group and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor having at least one oxime group or hydrazone group, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one COX-2 selective inhibitor having at least one oxime group or hydrazone group, optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention having at least one oxime group or hydrazone group can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

  该发明描述了具有至少一个肟基团或缩醛基团的新型环氧合酶2（COX-2）选择性抑制剂，以及包含至少一个具有至少一个肟基团或缩醛基团的环氧合酶2（COX-2）选择性抑制剂的新型组合物，以及可选地至少一个供体、转移或释放一氧化氮、刺激内源性一氧化氮合成、提高内源性内皮源性舒张因子水平或是一氧化氮合酶底物的化合物，和/或至少一个治疗剂。该发明还提供了包含至少一个具有至少一个肟基团或缩醛基团的COX-2选择性抑制剂的新型试剂盒，可选地硝化和/或亚硝化，以及可选地至少一个一氧化氮供体，和/或，可选地至少一个治疗剂的试剂盒。该发明的新型环氧合酶2选择性抑制剂具有至少一个肟基团或缩醛基团，可选地硝化和/或亚硝化。该发明还提供了治疗炎症、疼痛和发热的方法；用于治疗和/或改善COX-2选择性抑制剂的胃肠特性；促进伤口愈合；用于治疗和/或预防肾脏和/或呼吸道毒性；用于治疗和/或预防由于环氧合酶-2水平升高而导致的其他疾病；以及用于改善COX-2选择性抑制剂的心血管特性的方法。
• [EN] NITROSATED BENZOPYRAN COMPOUNDS AS NOVEL CYCLOOXYGENASE-2 SELECTIVE INHIBITORS<br/>[FR] COMPOSES BENZOPYRANNE NITROSES EN TANT QUE NOUVEAUX INHIBITEURS SELECTIFS DE LA CYCLOOXYGENASE-2
  申请人：PHARMACIA & UPJOHN CO LLC

  公开号：WO2006040676A1

  公开（公告）日：2006-04-20

  This invention specifically relates to novel cyclooxygenase 2 (COX-2) selective inhibitor compounds that donate, transfer or release nitric oxide, stimulate endogenous synthesis of nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase. Compounds of particular interest and their analogs defined by formula (I) wherein Z, X, R1, R2, R3, and R4 are as described in the specification. This invention also relates to pharmaceutical compositions and methods for treating COX-2 mediated disorders, such as inflammation and inflammation related disorders.

  这项发明特指与新型环氧合酶2（COX-2）选择性抑制剂化合物有关，这些化合物可以提供、转移或释放一氧化氮，刺激内源性一氧化氮的合成，提高内源性内皮源性舒张因子的水平，或者是一氧化氮合酶的底物。特别感兴趣的化合物及其由式（I）中定义的类似物，其中Z、X、R1、R2、R3和R4如规范中所述。这项发明还涉及用于治疗COX-2介导的疾病，如炎症和与炎症相关的疾病的药物组合物和方法。
• Piperazine derivatives and methods of use
  申请人：Chen J. Jian

  公开号：US20050014749A1

  公开（公告）日：2005-01-20

  Selected compounds are effective for treatment of pain and diseases, such as inflammation mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving pain, inflammation, and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

  所选化合物对于治疗疼痛和炎症介导的疾病等方面有效。该发明涵盖了新颖的化合物、类似物、前药和其药学上可接受的衍生物，以及用于预防和治疗涉及疼痛、炎症等疾病或其他疾病或病况的药物组合物和方法。该发明还涉及制备这类化合物的方法，以及在这类方法中有用的中间体。